EP4253374A1 - Deuterierter 2-arylheterocyclus-3-oxo-2,3-dihydropyridazin-4-carboxamid-inhibitor sowie herstellungsverfahren dafür und anwendung davon - Google Patents

Deuterierter 2-arylheterocyclus-3-oxo-2,3-dihydropyridazin-4-carboxamid-inhibitor sowie herstellungsverfahren dafür und anwendung davon Download PDF

Info

Publication number
EP4253374A1
EP4253374A1 EP21897208.1A EP21897208A EP4253374A1 EP 4253374 A1 EP4253374 A1 EP 4253374A1 EP 21897208 A EP21897208 A EP 21897208A EP 4253374 A1 EP4253374 A1 EP 4253374A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
group
deuterated
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21897208.1A
Other languages
English (en)
French (fr)
Inventor
Binhua Lv
Dawei Cui
Lianjun Liu
Xudong PANG
Chuanke CHAI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
Original Assignee
Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Suzhou Zelgen Biopharmaceutical Co Ltd, Shanghai Zelgen Pharmatech Co Ltd filed Critical Suzhou Zelgen Biopharmaceutical Co Ltd
Publication of EP4253374A1 publication Critical patent/EP4253374A1/de
Pending legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention belongs to the field of drugs, and particularly relates to a deuterated 2-arylheterocycle-3-oxo-2,3-dihydropyridazine-4-carboxamide inhibitor, a preparation method therefor and use thereof.
  • the aryl hydrocarbon receptor is a ligand-activated transcription factor involved in the regulation of various cellular processes, including cell proliferation, metabolism, immune regulation, etc.
  • AhR can affect cell signal transduction by interacting with various regulatory and signaling proteins, including PAS heterodimer partner ARNT (aryl hydrocarbon receptor nuclear translocator), chaperone and immune-like proteins (e.g., HSP90), AIP (aryl hydrocarbon receptor-interacting protein), p23, CK2 (casein kinase-2), PKC (protein kinase-C), etc.
  • AhR also interacts with hormone receptors, hypoxia, NF-KappaB, Rb protein-mediated signaling pathways, MAPK signaling pathways, EGFR signaling pathways, etc. It was discovered in a study that AhR is highly expressed in various tumors, such as lung cancer, colorectal cancer, head and neck squamous cell carcinomas, etc., and can play a key role in the regulation of immunosuppression in tumor microenvironment. A preclinical study showed that mice that are continuously activated spontaneously develop tumors.
  • AhR is expressed in many cells of the immune system, including dendritic cells (DCs), macrophages, T cells, NK cells, etc.
  • AhR plays an important role in immune regulation: (1) for example, the endogenous AhR ligand may promote the development of Treg cells in TME; (2) AhR promotes the differentiation of Th17 cells through multiple mechanisms; furthermore, AhR regulates the expression of Th17 by binding to the DRE sites on the Th17 promoter; AhR can also cooperate with Stat3 to induce the expression of the Ikaros family member Aiolos (IKZF3), reduce the expression of IL-2 and promote the generation of Th17 cells; (3) the interaction between AhR and c-Maf is critical for the development of mouse and human Tr1 regulatory cells; (4) AhR regulates B-cell differentiation and the like by inhibiting the transcription of B-cell early genes EBF1 and PAX5.
  • AhR Ah receptor ligands
  • Exogenous ligands such as PAH (polycyclic aromatic hydrocarbons), dioxins (e.g., TCDD) and polychlorinated biphenyls, etc.
  • PAH polycyclic aromatic hydrocarbons
  • dioxins e.g., TCDD
  • polychlorinated biphenyls etc.
  • AhR induces metabolic mechanisms, such as cytochrome p450 enzymes, etc. (CYP1A1, CYP1A2, CYP1B1, etc.), to eliminate the environmental toxins.
  • CYP1A1, CYP1A2, CYP1B1, etc. cytochrome p450 enzymes, etc.
  • a study showed that exogenous ligands, such as TCDD, etc., that activate AhR have been proved to play a role in many cellular processes, such as embryogenesis, tumorigenesis, inflammation, etc.
  • AhR can also bind to metabolites of tryptophan degradation.
  • Tryptophan metabolites such as kynurenine and kynurenic acid
  • IDO1/IDO2 indoleamine-2,3-dioxygenases 1 and 2
  • TDO2 tryptophan-2,3-dioxygenase 2
  • TDO2 is also strongly expressed in cancer, leading to the production of immunosuppressive kynurenines.
  • kynurenine activates AhR, inhibits the anti-tumor immune response by mediating tryptophan degradation downstream, and directly promotes the survival and viability of tumor cells, thus promoting tumor growth. Therefore, the AhR ligands produced by tumor cells act on the tumor cells and the lymphocytes in autocrine and paracrine manners respectively, thereby promoting the tumor growth.
  • AhR target proteins are pathologically associated with various diseases, there is also a need for novel AhR inhibitors for clinical treatment at present.
  • High-selectivity and high-activity AhR inhibitors can more effectively treat cancers and other diseases associated with abnormal AhR mediation and reduce the potential of off-target effect, so there is an urgent clinical demand on the AhR inhibitors.
  • the present invention aims to provide a class of novel compounds with a selective inhibition effect on AhR and/or better pharmacodynamic properties and use thereof.
  • a deuterated 3-oxo-2,3-dihydropyridazine-4-carboxamide compound having a structure of general formula (I), or a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof:
  • the compound has a structure of general formula (II): R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are as defined above.
  • R 1 is substituted or unsubstituted C 3 -C 10 cycloalkyl or substituted or unsubstituted saturated 4- to 10-membered heterocyclyl.
  • the compound has a structure of general formula (III):
  • R 11 , R 12 , R 13 , and R 14 are each independently selected from the group consisting of the following substituted or unsubstituted groups: H, deuterium, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and 4- to 6-membered heterocyclyl; and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are as defined above.
  • R 11 or R 12 is selected from the group consisting of: D, CN, CH 3 , CD 3 , CF 3 , isopropyl, C 3 -C 6 cycloalkyl, and 4- to 6-membered heterocyclyl.
  • the carbon atom connected with R 11 or R 12 is a chiral carbon atom, the configuration of which is R-type or S-type.
  • the compound has a structure of formula (IV):
  • R 11 , R 12 , R 13 , and R 14 are each independently selected from the group consisting of the following substituted or unsubstituted groups: H, deuterium, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and 4- to 6-membered heterocyclyl; and R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , and R 10 are as defined above.
  • R 3 is selected from the group consisting of: CH 3 and CD 3 .
  • R 13 and R 14 are each independently deuterium.
  • R 2 is D.
  • R 3 is CD 3 .
  • R 9 and R 10 are each independently deuterium.
  • R 4 , R 5 , R 6 and R 8 are each independently deuterium.
  • R 4 and R 6 are each independently deuterium.
  • R 5 and R 8 are each independently deuterium.
  • the compound is selected from the group consisting of:
  • the method comprises the steps of:
  • a pharmaceutical composition comprising: i) one or more of the compound having the structure of general formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof according to the first aspect of the present invention; and ii) a pharmaceutically acceptable carrier.
  • a fourth aspect of the present invention there is provided use of the deuterated 3-oxo-2,3-dihydropyridazine-4-carboxamide compound having the structure of general formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof according to the first aspect of the present invention or the pharmaceutical composition according to the third aspect of the present invention in the preparation of a pharmaceutical composition for preventing and/or treating an AhR-mediated disease.
  • the deuterated 3-oxo-2,3-dihydropyridazine-4-carboxamide compound having the structure of general formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof according to the first aspect of the present invention or the pharmaceutical composition according to the third aspect of the present invention in the preparation of a pharmaceutical composition for preventing and/or treating an AhR-mediated disease
  • the disease associated with abnormal AhR mediation is a tumor or a disorder.
  • the disease is selected from the group consisting of: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, melanoma, lymphoma, leukemia, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, and skin cancer.
  • a method for inhibiting AhR comprising the step of: administering an effective amount of the compound of general formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof according to the first aspect of the present invention or administering the pharmaceutical composition according to the third aspect of the present invention to a patient in need.
  • FIG. 1 is a graph of tumor growth in a pharmacodynamic test of anti-tumor activity.
  • the inventor unexpectedly discovered a class of novel compounds with a selective inhibition effect on AhR and/or better pharmacodynamic properties. On this basis, the present invention is achieved.
  • alkyl refers to a linear or branched or cyclic alkyl group containing 1 to 20 carbon atoms (e.g., 1 to 18 carbon atoms, particularly 1 to 18 carbon atoms.
  • Typical "alkyl” groups include methyl, ethyl, propyl, isopropyl, n -butyl, t -butyl, isobutyl, pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc.
  • C 1 -C 18 alkyl refers to a linear or branched or cyclic alkyl group containing 1 to 18 carbon atoms, such as methyl, ethyl, propyl, isopropyl n -butyl, t -butyl, isobutyl (e.g., n -pentyl, isopentyl, n -hexyl, isohexyl, n -heptyl, and isoheptyl.
  • “Substituted alkyl” means that one or more positions in an alkyl group are replaced particularly by 1 to 4 substituents, and the substitution may occur at any position.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon group including 1 to 4 rings each containing 3 to 8 carbon atoms. "Substituted cycloalkyl” means that one or more positions in a cycloalkyl group are replaced particularly by 1 to 4 substituents, and the substitution may occur at any position.
  • Typical substituents also include spiro-, bridged- or fused-ring substituents, particularly spiro-cycloalkyl, spiro-cycloalkenyl, spiro-heterocyclic ring (excluding heteroaromatic ring), bridged-cycloalkyl, bridged-cycloalkenyl, bridged-heterocyclic ring (excluding heteroaromatic ring), fused-cycloalkyl, fused-cycloalkenyl, fused-heterocyclyl, or fused aromatic ring group, and the above cycloalkyl, cycloalkenyl, heterocyclyl and heterocycloaryl groups may be optional for substitution. Any two or more atoms on the rings may be further attached to other cycloalkyl, heterocyclyl, aryl and heteroaryl groups.
  • heterocyclyl refers to a fully saturated or partially unsaturated cyclic group (including but not limited to, for example, a 3- to 7-membered monocyclic, 6- to 11-membered bicyclic or 8- to 16-membered tricyclic ring system), with at least one heteroatom being present in the ring having at least one carbon atom.
  • Each heterocyclic ring containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, among which the nitrogen atoms or the sulfur atoms may be oxidized and the nitrogen atoms may also be quaternized.
  • the heterocyclyl group may be attached to any heteroatom or residue of a carbon atom of the ring or ring system molecule.
  • Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidinonyl, tetrahydropyranyl, morphinyl, thiomorpholinyl, thiomorpholinosulfoxyl, thiomorpholinosulfuryl, 1,
  • Polycyclic heterocyclyl groups include spiro-, fused- and bridged-heterocyclyl groups; the spiro-, fused- and bridged-heterocyclyl groups involved are optionally attached to other groups by single bonds or further attached to other cycloalkyl, heterocyclyl, aryl and heteroaryl groups by any two or more atoms on the rings; the heterocyclyl group may be substituted or unsubstituted, and when it is substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, sulfhydryl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carb
  • aryl refers to an aromatic cyclic hydrocarbon group having 1 to 5 rings, particularly monocyclic and bicyclic groups, such as phenyl, biphenyl, or naphthyl. If two or more aromatic rings (bicyclic rings, etc.) are contained, the aromatic rings of the aryl group may be attached by single bonds (e.g., biphenyl) or fused (e.g., naphthalene, anthracene, etc.). "Substituted aryl” means that one or more positions in an aryl group are replaced particularly by 1 to 3 substituents, and the substitution may occur at any position.
  • Typical substituents may be optional for substitution.
  • Typical substituents also include fused-ring substituents, particularly fused-cycloalkyl, fused-cycloalkenyl, fused-heterocyclyl, or fused aromatic ring group, and the above cycloalkyl, cycloalkenyl, heterocyclyl and heterocycloaryl groups may be optional for substitution.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and sulfur.
  • the heteroaryl group is preferably a 5- to 10-membered ring, more preferably a 5- or 6-membered ring, e.g., pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, etc.
  • Heteroaryl may be substituted or unsubstituted, and when it is substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, sulfhydryl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate group.
  • halogen or "halo-" refers to chlorine, bromine, fluorine, and iodine.
  • halo refers to a substitution by halogen.
  • deuterated refers to a substitution by deuterium.
  • hydroxyl refers to a group with a structure OH.
  • nitro refers to a group with a structure NO 2 .
  • cyano refers to a group with a structure CN.
  • esters refers to a group with a structure -COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or a heterocyclic ring or a substituted heterocyclic ring.
  • amino refers to a group with a structure -NRR', wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or a heterocyclic ring or a substituted heterocyclic ring, as defined above. R and R' may be the same or different in a dialkylamine moiety.
  • amido refers to a group with a structure -CONRR', wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or a heterocyclic ring or a substituted heterocyclic ring, as defined above. R and R' may be the same or different in a dialkylamine moiety.
  • sulfonamido refers to a group with a structure -SO 2 NRR', wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or a heterocyclic ring or a substituted heterocyclic ring, as defined above. R and R' may be the same or different in a dialkylamine moiety.
  • ureido refers to a group with a structure -NRCONR'R", wherein R, R' and R" may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or a heterocyclic ring or a substituted heterocyclic ring, as defined above. R, R' and R" may be the same or different in a dialkylamine moiety.
  • alkylaminoalkyl refers to a group with a structure -RNHR', wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or a heterocyclic ring or a substituted heterocyclic ring, as defined above. R and R' may be the same or different.
  • dialkylaminoalkyl refers to a group with a structure -RNHR'R", wherein R, R' and R" may independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or a heterocyclic ring or a substituted heterocyclic ring, as defined above. R, R' and R" may be the same or different in a dialkylamine moiety.
  • heterocyclylalkyl refers to a group with a structure -RR', wherein R may independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, or aryl or substituted aryl, and R' represents a heterocyclic ring or a substituted heterocyclic ring.
  • substitute means that one or more hydrogen atoms on a specific group are substituted with specific substituents.
  • the specific substituents are those described correspondingly in the preceding text or those presented in each example.
  • a substituted group may have a substituent selected from a specific group at any substitutable positions of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those stable or chemically available.
  • the substituents are for example (but not limited to): halogen, hydroxy, cyano, carboxyl (-COOH), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C 1 -C 8 formyl, C 2 -C 10 acyl, C 2 -C 10 ester, amino, C 1 -C 6 alkoxy, C 1 -C 10 sulfonyl, C 1 -C 6 ureido, etc.
  • substituents are non-terminal substituents, they are subunits of the corresponding groups, e.g., alkyl corresponding to alkylene, cycloalkyl corresponding to cycloalkylene, heterocyclyl corresponding to heterocyclylene, and alkoxy corresponding to alkyleneoxy.
  • the present invention provides a deuterated 3-oxo-2,3-dihydropyridazine-4-carboxamide compound having a structure of general formula (I), or a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof:
  • salts which may be formed by the compound in the present invention are also within the scope of the present invention.
  • the compound of the present invention should be understood to include salts thereof.
  • the term "salt” used herein refers to an acidic or basic salt formed from an inorganic or organic acid and a base.
  • a basic moiety it includes, but is not limited to, pyridine or imidazole; when the compound of the present invention contains an acidic moiety, it includes, but is not limited to, carboxylic acid; and zwitter-ions (“inner salts”) that may be formed are included within the scope of the term "salt”.
  • salts are preferred, although other salts are useful in, for example, isolation or purification step of the preparation process.
  • the compound of the present invention may form salts.
  • the compound (I) reacts with an amount (e.g., an equivalent amount) of acid or base, and a salt is isolated by salting out from a medium or by lyophilization in aqueous solution.
  • the compound of the present invention may contain basic moieties, including but not limited to amine or pyridine or imidazole rings, which may form salts along with organic or inorganic acids.
  • Typical salts which may be formed by acids include acetate (e.g., formed with acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, diglycolate, laurylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydriodate, hydroxyethanesulfonate (e.g., 2-hydroxy
  • Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts along with various organic or inorganic bases.
  • Typical salts formed by bases include ammonium salts, alkali metal salts, such as sodium salt, lithium salt, and potassium salt, alkaline earth metal salts, such as calcium salt and magnesium salt, salts formed with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, hydrabamine (a salt formed with N, N -di(dehydroabietyl)ethylenediamine), N -methyl-D-glucamine, N -methyl-D-glucamide, and t -butylamine, and salts formed with amino acids (e.g., arginine, lysine, etc.).
  • organic bases e.g., organic amines
  • benzathine dicyclohexylamine
  • hydrabamine a salt formed with
  • the basic nitrogen-containing groups may be combined with halide quaternary ammonium salts, such as small-molecular alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, methyl, ethyl, propyl, and butyl bromides, and methyl, ethyl, propyl, and butyl iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long-chain halides (e.g., decyl, dodecyl, tetradecyl, and tetradecyl chlorides, decyl, dodecyl, tetradecyl, and tetradecyl bromides, and decyl, dodecyl, tetradecyl, and tetradecyl iodides), a
  • Prodrugs and solvates of the compounds of the present invention also fall within the scope of the present invention.
  • the term "prodrug” used herein refers to a compound that undergoes chemical transformation through a metabolic or chemical process to give a compound, salt, or solvate of the present invention when used in the treatment of a related disease.
  • the compounds of the present invention include solvates, such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (e.g., amides and imine ethers). All these tautomers are part of the present invention.
  • Stereoisomers of all the compounds e.g., those asymmetric carbon atoms which may exist due to various substitutions), including enantiomeric and diastereomeric forms thereof, shall fall within the scope of the present invention.
  • the independent stereoisomers of the compounds of the present invention may not be present in combination with other isomers (e.g., having special activity as a pure or substantially pure optical isomer), or may be present as a mixture, such as a racemate, or as a mixture formed with all or part of the other stereoisomers.
  • the chiral center of the present invention has two configurations, S or R, as defined by the recommendation of the International Union of Pure and Applied Chemistry (IUPAC) in 1974.
  • racemic forms may be resolved by physical methods, such as fractional crystallization, separation or crystallization of derived diastereoisomers, or chiral column chromatography.
  • Individual optical isomers may be obtained from racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by crystallization.
  • the content, by weight, of the compound of the present invention, which is obtained by preparation, separation and then purification, is equal to or greater than 90%, e.g., is equal to or greater than 95%, or is equal to or greater than 99% ("very pure" compound), as listed in the text description.
  • very pure compounds of the present invention are also part of the present invention.
  • All configurational isomers of the compounds of the present invention fall within the scope of the present invention, whether in mixture, pure or very pure form.
  • the definition of the compound of the present invention includes cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.
  • groups and substituents can be selected to provide stable moieties and compounds.
  • Certain compounds of the present invention may exist in the form of specific geometric isomers or stereisomers.
  • the present invention encompasses all the compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures.
  • the asymmetric carbon atoms may represent substituents, such as alkyl groups. All the isomers and mixtures thereof are encompassed by the present invention.
  • the ratio of isomers in a mixture of the isomers may be varied.
  • a mixture of only two isomers there may be the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, ratios of all isomers being within the scope of the present invention.
  • Similar ratios which are easily understood by those of ordinary skill in the art, as well as ratios in mixtures of more complex isomers, are also within the scope of the present invention.
  • the present invention also includes isotopically labeled compounds, equivalent to the disclosure of the original compounds herein. In fact, however, it usually occurs that one or more atoms are substituted with atoms with different atomic weights or mass numbers.
  • isotopes that may be listed as the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl.
  • the compounds or the enantiomers, diastereomers, isomers or pharmaceutically acceptable salts or solvates (containing the isotopes of the above compounds or other isotope atoms) thereof in the present invention are all within the scope of the present invention.
  • Certain isotopically labeled compounds of the present invention e.g., including radioisotopes of 3 H and 14 C, are also useful in an tissue distribution study of drugs and substrates. Tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are easy to prepare and detect. They are the first choice among isotopes.
  • the isotopically labeled compounds may be prepared by the general method of replacing a readily available isotopically labeled reagent with a non-isotopically labeled reagent according to the solutions disclosed in the examples.
  • a specific enantiomer of a compound of the present invention may be prepared by asymmetric synthesis or derivatised with a chiral auxiliary, the resulting diastereomeric mixture is separated, and the chiral auxiliary is then removed to give a pure enantiomer.
  • a diastereomer salt can be formed with an appropriate optically active acid or base, and separation is carried out by a conventional means such as fractional crystallization or chromatography to give a pure enantiomer.
  • the compounds of the present invention may be substituted with any number of substituents or functional groups to expand the scope of the present invention.
  • substitute whether appearing before or after the term “optionally”, means that the hydrogen radical is replaced by a substituent with a specific structure in a general formula containing the substituent in a formulation of the present invention.
  • substituents may be the same or different.
  • substitute used herein includes substitution by all allowed organic compounds.
  • allowed substituents include acyclic, cyclic, branched, unbranched, carbocyclic, heterocyclic, aromatic, and nonaromatic organic compounds.
  • the heteroatom nitrogen may have a hydrogen substituent or any allowed organic compound mentioned above to supplement its valence state.
  • the present invention is not intended to limit organic compounds allowed for substitution in any way.
  • the present invention believes that the combination of substituents and variable groups is excellent in the treatment of diseases, such as infectious diseases or proliferative diseases, in the form of stable compounds.
  • stable used herein means that a compound is stable enough to maintain the structural integrity of the compound for a long time when detected long enough, preferably maintaining efficacy long enough, for the above purpose herein.
  • Metabolites of the compounds and the pharmaceutically acceptable salts thereof involved in the present application, as well as prodrugs that can be transformed into the structures of the compounds and the pharmaceutically acceptable salts thereof involved in the present application in vivo, are also included in the claims of the present application.
  • the process for preparing the compound of the present invention is as follows, in which the materials and reagents used are commercially available unless otherwise specified.
  • the pharmaceutical composition disclosed herein is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular diseases, infection, immunological diseases, and metabolic diseases.
  • the compound of general formula (I) may be administered in combination with other drugs known to treat or ameliorate similar conditions. During administration in combination, the administration route and dose of the original drug may be kept unchanged, and the compound of formula I may be administered simultaneously or subsequently. When the compound of formula I is administered simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I may be preferably used. The administration of the drugs in combination also includes the administration of the compound of formula I and one or more other known drugs in overlapping time periods. When the compound of formula I is administered in combination with one or more other drugs, the doses of the compound of formula I or the known drugs may be lower than those of them administered alone.
  • Drugs or active ingredients that may be administered in combination with the compound of general formula (I) include, but are not limited to: PD-1 inhibitors (e.g., nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM009, or biologically similar drugs thereof), PD-L1 inhibitors (e.g., durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311, or biologically similar drugs thereof), CD20 antibodies (e.g.
  • PD-1 inhibitors e.g., nivolumab, pe
  • CD47 antibodies e.g. Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, and IMM01
  • ALK inhibitors e.g.
  • PI3K inhibitors e.g. Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.
  • BTK inhibitors e.g. Ibrutinib , Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.
  • EGFR inhibitors e.g.
  • VEGFR inhibitors e.g. Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib, Sunitinib, Donafenib, etc.
  • HDAC inhibitors e.g.
  • CDK inhibitors e.g. Palbociclib, Ribociclib, Abemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.
  • MEK inhibitors e.g. Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.
  • mTOR inhibitors e.g. Vistusertib, etc.
  • SHP2 inhibitors e.g. RMC-4630, JAB-3068, TNO155, etc.
  • Dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): injections, tablets, capsules, aerosols, suppositories, pellicles, dripping pills, topical liniment, controlled-release or sustained-release or nanometer preparations.
  • the pharmaceutical composition of the present invention contains the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier in a safe and effective amount range, wherein the "safe and effective amount” means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose.
  • the "dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. “Compatible” herein means that the components of the composition are capable of intermixing with the compound of the present invention and with each other, without significantly diminishing the pharmaceutical efficacy of the compound.
  • the pharmaceutically acceptable carriers include cellulose and derivatives thereof (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid and magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween ® ), wetting agents (e.g., sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and derivatives thereof e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin talc
  • administration routes of the compound or pharmaceutical composition of the present invention are not specifically limited, typically including (but not limited to): oral administration, intratumoral administration, rectal administration, parenteral (intravenous, intramuscular or subcutaneous) administration, and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, pulvises, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or calcium phosphate, or mixed with the following ingredients: (a) fillers or solubilizers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow-dissolving agents, such as paraffin; (f) absorption accelerators, such as a quaternary amine compound; (g) wetting
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules, can be prepared using coatings and shells, such as enteric coatings and other materials well known in the art. They may comprise opacifying agents, and the active compound or compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components which can be used are polymeric substances and wax-based substances. If necessary, the active compound can also be in microcapsule form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and tinctures.
  • the liquid dosage forms may comprise inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanedi
  • composition may also comprise adjuvants, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and perfuming agents.
  • adjuvants such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and perfuming agents.
  • the suspensions may comprise suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methylate and agar, or mixtures of these substances, etc.
  • suspending agents e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methylate and agar, or mixtures of these substances, etc.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for redissolving into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms of the compound of the present invention for topical administration include ointments, pulvises, patches, sprays, and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be needed if necessary.
  • the therapeutic method of the present invention may be applied alone or in combination with other therapeutic means or therapeutic drugs.
  • a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) to be treated, wherein the administration dose is a pharmaceutically effective administration dose.
  • a mammal e.g., a human
  • the daily administration dose is usually 1-2000 mg, preferably 50-1000 mg.
  • factors as the route of administration, the health condition of the patient and the like will also be considered, which are well known to skilled physicians.
  • the present invention also provides a method for preparing the pharmaceutical composition, which comprises the step of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) of the present invention or the crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof to form the pharmaceutical composition.
  • the present invention also provides a treatment method, which comprises the step of: administering to a subject to be treated the compound of general formula (I) of the present invention or the crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the pharmaceutical composition of the present invention for selectively inhibiting AhR.
  • the present invention mainly has the following advantages:
  • the compound structure of the present invention is determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
  • NMR is determined using a Bruker AVANCE-400 nuclear magnetic resonance instrument, with deuterated dimethylsulfoxide (DMSO-d 6 ), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) and the like as determination solvents and tetramethylsilane (TMS) as an internal standard, and chemical shifts are measured in unit of 10 -6 (ppm).
  • DMSO-d 6 deuterated dimethylsulfoxide
  • CD 3 COCD 3 deuterated acetone
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • LC-MS Liquid chromatography-mass spectrometry
  • Qingdao GF254 silica gel plate is adopted as a thin-layer chromatography (TLC) silica gel plate, 0.15-0.20 mm adopted for TLC and 0.4-0.5 mm adopted for the preparation of thin-layer chromatography.
  • Qingdao silica gel with 200-300 meshes is generally adopted as a carrier in column chromatography.
  • Step 1 Preparation of 4-bromo-1-(methyl- d 3)-1 H -pyrazole
  • Step 2 Preparation of Di- t -butyl 1-(1-(methyl- d 3)-1 H -pyrazole-4-yl)hydrazino-1,2-dicarboxylate
  • reaction solution was stirred for 2 h while the temperature was kept, and the reaction was then quenched with aqueous ammonium chloride solution.
  • the resulting mixture was warmed to room temperature, and the mixture was added with 100 mL of water and then extracted twice with ethyl acetate.
  • the combined organic phases were washed once with saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated to become dry.
  • the resulting residue was slurried with ethyl acetate/petroleum ether to give the target product (1.6 g). ;
  • Step 1 Preparation of Methyl 6-(4-chlorophenyl)-2-(1-(methyl- d 3)-1 H -pyrazole-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate
  • Step 2 Preparation of Methyl 6-(4-chlorophenyl)-2-(1-(methyl- d 3)-1 H -pyrazole-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate
  • Step 3 Preparation of 6-(4-chlorophenyl)-2-(1-(methyl- d 3)-1 H -pyrazole-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate
  • Step 4 Preparation of ( S )-6-(4-chlorophenyl)- N -(1-hydroxypropan-2-yl)-2-(1-(methyl- d 3)-1 H -pyrazole-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
  • Example 8 Preparation of ( S )-6-(4-chlorophenyl)- N -(1-hydroxypropan-2-yl-1,1- d 2)-2-(1-(methyl- d 3)-1 H -pyrazole-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
  • Example 14 Preparation of ( S )-6-(4-chlorophenyl)- N -(1-hydroxypropan-2-yl-1,1,2,3,3,3- d 6)-2-(1-(methyl- d 3)-1 H -pyrazole-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
  • the compounds 1-chlorobenzene-2,3,4,5,6- d 5 (5 g, 42.5 mmol) and dichloromethane (35 mL) were added in sequence into a round-bottom flask.
  • the reaction solution was cooled to 0 °C in an ice bath, the compound chloroacetyl chloride (5.8 g, 51 mmol) was then added, and finally aluminum trichloride was added (9 g, 68 mmol).
  • the resulting reaction solution reacted at 0 °C for 2 h, and was then added into ice water for quenching and extracted with dichloromethane.
  • the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated to give the target compound (7.4 g, yield: 90.7%).
  • the product was directly used in the next reaction without purification.
  • Step 3 Preparation of Methyl 6-(4-chlorophenyl-2,3,5,6- d 4)-2-(1-methyl-1 H -pyrazole-4-yl)-3-formyl-2,3,4,5-tetrahydropyridazine-4-carboxylate
  • Step 4 Preparation of Methyl 6-(4-chlorophenyl-2,3,5,6- d 4)-2-(1-methyl-1 H -pyrazole-4-yl)-3-formyl-2,3-dihydropyridazine-4-carboxylate
  • Step 5 Preparation of ( S )-6-(4-chlorophenyl-2,3,5,6- d 4)- N -(1-hydroxypropan-2-yl)-2-(1-methyl-1 H -pyrazole-4-yl)-3-formyl-2,3-dihydropyridazine-4-carboxamide
  • Example 17 Preparation of ( S )-6-(4-chlorophenyl-2,3,5,6-d4)- N -(1-hydroxypropan-2-yl-1,1- d 2)-2-(1-(methyl- d 3)-1 H -pyrazole-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
  • Wavelength Excitation Filter 400 Emission Filter 1 460 Emission Filter 2 535 Dichroic Mirror Beta lactamase D425/490
  • Example 2 Example 7
  • Example 8 Administration dose 2 mg/kg 2 mg/kg 2 mg/kg 2 mg/kg AUC 0-t ng.h/mL 624 990 736 1394 Cmax ng/mL 99.5 146 96.6 230
  • the compounds of the examples obtained by the present invention show better metabolic properties in the rat body, and have higher plasma exposures AUC and Cmax, thus having better pharmaceutical efficacy.
  • mice After male ICR mice weighing about 20-30 g were fasted overnight, the mice were gavaged with 2 mg/kg of a solution of the compound of the present invention [CMC/TW80 as a carrier]. Blood was collected 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24 h after the administration of the compound of the present invention, respectively, and the concentration of the compound of the present invention in plasma was determined by LC/MS/MS.
  • the compounds of the examples obtained by the present invention show better metabolic properties in the mouse body, and have higher plasma exposure AUC, thus having better pharmaceutical efficacy.
  • the compounds of the examples obtained by the present invention show better metabolic properties in the dog body, and have higher plasma exposures AUC and Cmax, thus having better pharmaceutical efficacy.
  • mice 5 ⁇ 10 5 /100 uL of mouse colon cancer cells CT26.WT were subcutaneously inoculated into the right back of nude mice. The mice were monitored daily for health condition, and the measurement was started when tumors grew to be palpable. The tumor volume was calculated by adopting the following formula: 0.5 ⁇ L ⁇ W 2 , wherein L and W represent tumor length and width, respectively. When the tumor grew to about 50 mm 3 , the mice were randomly grouped. The mice were gavaged daily with a solution of the compound at a corresponding dose (30 mg/Kg) [CMC/TW80 as a carrier], and at the same time, the general state of the mice was monitored.
  • a solution of the compound at a corresponding dose (30 mg/Kg) [CMC/TW80 as a carrier
  • mice were weighed twice in the first week, and the tumor volume was measured twice; from the second week, the mice were weighed three times a week, and the tumor volume was measured three times.
  • Table 4 Pharmacodynamic Test and Evaluation of Anti-tumor Activity Group TV (mm 3 ) (Tumor Volume) Day 0 TV (mm 3 ) (Tumor Volume) Day 17 %TGI (Tumor Growth Inhibition) Blank control group 55.55 2200.23 / Example 8 55.68 1117.93 50.5% BAY-2416964 55.81 1670.91 24.7%
EP21897208.1A 2020-11-27 2021-11-29 Deuterierter 2-arylheterocyclus-3-oxo-2,3-dihydropyridazin-4-carboxamid-inhibitor sowie herstellungsverfahren dafür und anwendung davon Pending EP4253374A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011367513.8A CN114539221A (zh) 2020-11-27 2020-11-27 氘代2-芳杂环-3-氧-2,3-二氢哒嗪-4-甲酰胺类抑制剂及其制备方法和应用
PCT/CN2021/134146 WO2022111708A1 (zh) 2020-11-27 2021-11-29 氘代2-芳杂环-3-氧-2,3-二氢哒嗪-4-甲酰胺类抑制剂及其制备方法和应用

Publications (1)

Publication Number Publication Date
EP4253374A1 true EP4253374A1 (de) 2023-10-04

Family

ID=81668265

Family Applications (1)

Application Number Title Priority Date Filing Date
EP21897208.1A Pending EP4253374A1 (de) 2020-11-27 2021-11-29 Deuterierter 2-arylheterocyclus-3-oxo-2,3-dihydropyridazin-4-carboxamid-inhibitor sowie herstellungsverfahren dafür und anwendung davon

Country Status (5)

Country Link
US (1) US20240002362A1 (de)
EP (1) EP4253374A1 (de)
JP (1) JP2023551019A (de)
CN (2) CN114539221A (de)
WO (1) WO2022111708A1 (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114835687B (zh) * 2021-04-02 2023-09-05 北京华森英诺生物科技有限公司 AhR抑制剂

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JOP20190193A1 (ar) * 2017-02-09 2019-08-08 Bayer Pharma AG ممركبات 2-أريل غير متجانس-3-أكسو-2، 3-ثنائي هيدرو بيريدازين-4-كربوكساميد لمعالجة السرطان

Also Published As

Publication number Publication date
US20240002362A1 (en) 2024-01-04
WO2022111708A1 (zh) 2022-06-02
JP2023551019A (ja) 2023-12-06
CN114539221A (zh) 2022-05-27
CN116583518A (zh) 2023-08-11

Similar Documents

Publication Publication Date Title
US20210163464A1 (en) Pyridine compound
WO2021228161A1 (zh) 烷氧基烷基取代杂环基类抑制剂及其制备方法和应用
WO2022161480A1 (zh) 取代双环并芳杂环胺类抑制剂及其制备方法和应用
TWI832539B (zh) 用作ｃｄｋ７激酶抑制劑的化合物及其應用
EP3590941A1 (de) Harnstoffsubstituierte aromatische ringverbundene dioxanchinazolin- und -verbundene dioxanchinolinverbindungen, herstellungsverfahren und dafür und verwendung davon
EP4050008A1 (de) Pyridazinon- oder pyridazinverbindung und derivat sowie pharmazeutische zusammensetzung davon
WO2021098859A1 (zh) 氮杂七元环类抑制剂及其制备方法和应用
WO2022166592A1 (zh) 取代嘧啶并吡啶酮类抑制剂及其制备方法和应用
EP4253374A1 (de) Deuterierter 2-arylheterocyclus-3-oxo-2,3-dihydropyridazin-4-carboxamid-inhibitor sowie herstellungsverfahren dafür und anwendung davon
CN108699030B (zh) 一类取代的氨基六元氮杂环类化合物及其制备和用途
WO2020224626A1 (zh) 用作激酶抑制剂的化合物及其应用
CN110357858B (zh) 具有穿过血脑屏障能力的5取代二氟哌啶化合物
US20240025908A1 (en) Compound used as kinase inhibitor and use thereof
US20230095530A1 (en) Compound used as ret kinase inhibitor and application thereof
WO2022143695A1 (zh) 磺酰胺类抑制剂及其制备方法和应用
CN117003737A (zh) 取代的咪唑苯基甲酮类化合物及其衍生物和药物组合物
CN114380805A (zh) 取代苯并或吡啶并嘧啶胺类抑制剂及其制备方法和应用
WO2024008083A1 (zh) 用作cdk7激酶抑制剂的化合物及其应用
WO2016153394A1 (ru) Применение новых химических соединений (варианты) в качестве ингибиторов nuak1 киназы для лечения онкологических заболеваний
WO2024051702A1 (zh) 用作cdk4激酶抑制剂的化合物及其应用
CN114907324A (zh) 取代苯并或吡啶并嘧啶胺类抑制剂及其制备方法和应用
WO2023039532A1 (en) Pi3k-alpha inhibitors and methods of use thereof
CN117820305A (zh) 杂环取代喹唑啉及其制备方法和应用
CN113354630A (zh) 一种5,6-二氢苯并[h]喹唑啉类化合物及其应用

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20230621

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)